Sustained administration of the antidepressant venlafaxine in rats: pharmacokinetic and pharmacodynamic findings

Rats were administered venlafaxine (10 mg/kg per day) for 14 days by using subcutaneously implanted osmotic minipumps. The present study assessed the distribution of VEN in different compartments, whether the VEN concentratio n in the compartments correlated, the effect of VEN on dialysate monoamine levels and on the spontaneous open-field behavior, and possible relations b etween the pharmacokinetic and pharmacodynamic parameters. The venlafaxine level in serum after sustained treatment was about 25% of t he concentration in brain parenchyma and much higher than in brain dialysat e. There was a clear correlation between venlafaxine concentrations in bloo d and brain compartments. The sustained venlafaxine challenge resulted in h igher neocortical concentration of serotonin and noradrenaline, lower 5-hyd roxyindole-3-acetic acid levels and increased locomotor activity in the cen tral part of the test arena as compared to controls. No correlations were f ound between the venlafaxine concentration and brain monoamine parameters o r the open-field behaviors. We conclude that, although species differences in pharmacokinetic propertie s for venlafaxine between rat and man exist, the pharmacokinetic correlatio ns found after sustained treatment add information to the in vivo nature of the drug. Also, more studies like the present need to be performed to find the pharmacokinetic/pharmacodynamic interrelations for drugs like VEN.